A variety of man-made, inorganic particles are sources of environmental and occupational lung diseases including pulmonary fibrosis and asthma. A key feature of these diseases is mesenchymal cell (fibroblast and smooth muscle cell) hyperplasia. We postulate that the platelet-derived growth factor (PDGF) receptor system is pivotal to the progression of these diseases. Fibrogenic particles (asbestos) and air pollution particulate matter (PM) cause airway inflammation by inducing macrophages to produce several cytokines including interleukin-1b (IL-1b), basic fibroblast growth factor (bFGF) and transforming growth factor betal (TGF-bl). We have shown that IL-1b and bFGF upregulate the PDGF alpha receptor and increase the mitogenic and chemotactic response of fibroblasts and airway smooth muscle cells to PDGF-AA, -AB and -BB. TGF- b1 down-regulates the PDGF receptor system. However, supernatants obtained from particle-stimulated macrophages which contain IL-1b, bFGF and TGF-b1 are strong inducers of the PDGF receptor. Furthermore, we discovered that bacterial wall components (endotoxin) and metals (e.g., vanadium) induce PDGF receptor upregulation and this may be significant since many air pollution PM are associated with surface-adhered endotoxin and metals. Thus, inhaled particles that cause fibroproliferative lung disease do so in part by activating macrophage populations in the lung to secrete cytokines that signal up-regulation of the PDGF receptor system on mesenchymal cells. Cells possessing up-regulated PDGF alpha receptor are hyper-responsive to the mitogenic and chemotactic effects of PDGF. We also reported that the mitogenic and chemotactic potential of PDGF isoforms is regulated by a2M, a proteinase inhibitor secreted by lung fibroblasts and macrophages. a2M selectively controls the PDGF-B chain dimers and serves to clear and inactivate GF through the a2M- receptor. We postulate that inorganic particles interfere with regulatory mechanisms (receptors and binding proteins) that normally control the biological activity of PDGF during tissue repair and maintenance. When these regulatory mechanisms are in place, inflammation following injury can be resolved and tissue is repaired. However, dysfunction of these regulatory mechanisms causes a fibrogenic response.